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Population Pharmacokinetics of Melphalan in a Large Cohort of Autologous and Allogeneic Hematopoietic Cell Transplantation Recipients: Towards Individualized Dosing Regimens

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Abstract

Background and Objectives

High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing.

Methods

Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM.

Results

Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity.

Conclusions

The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.

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Author information

Authors and Affiliations

  1. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Gunjan L. Shah, Nancy Cruz Sitner, Anna Alperovich, Josel Ruiz, Parastoo Dahi, Roni Tamari, Sergio A. Giralt & Michael Scordo

  2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Gunjan L. Shah, Parastoo Dahi, Roni Tamari, Sergio A. Giralt & Michael Scordo

  3. Stem Cell Transplantation and Cellular Therapies Program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jaap Jan Boelens

  4. Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Jaap Jan Boelens

  5. Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Dean Carlow & Ryan Schofield

  6. Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew Lin & Anthony Proli

  7. Pediatric Hematopoeitic Cell Transplantation Program, Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands

    Rick Admiraal

  8. Department of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands

    Rick Admiraal

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  1. Gunjan L. Shah
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Corresponding author

Correspondence to Rick Admiraal.

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Funding

The study was supported by funding from the Sawiris Family Research Fund, Melvin Berlin Family Fund for Myeloma Research, A.C. Israel Foundation, and the Donna and Patrick Martin Foundation. This research was supported in part by National Institutes of Health award number P01 CA23766 and National Institutes of Health/National Cancer Institute Cancer Center Support grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was performed independently of all funders.

Conflicts of interest/Competing interests

GS reports research funding from Janssen and Amgen unrelated to the current project. MS has served as a consultant for McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; has received research funding from Angiocrine Bioscience, Inc. and Omeros Corporation; has served on an advisory board for Kite, a Gilead Company; and has served as a CME speaker for i3Health, all unrelated to the current project. JB has received honoraria for consulting for Race Oncology, AvroBio, Omeros, Sanofi, Advanced Clinical, and BlueRock, all unrelated to the current project. SG has consulted for and received research funding from Amgen, Actinium, Celgene, Johnson & Johnson, and Takeda; has consulted for Jazz Pharmaceuticals, Novartis, Kite, and Spectrum Pharmaceuticals; and has received research funding from Miltenyi unrelated to the current project. MS has received research support from Angiocrine Bioscience, Inc. and Omeros Corporation; has consulted for Angiocrine Bioscience, Inc., Omeros Corporation and McKinsey & Company; has advised for Kite , a Gilead Company; and received a speaking engagement from i3Health. RA has received research grants from Sanofi, unrelated to the current project.

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Availability of data and material

The data and materials for this study are not available.

Code availability

The model codes are available upon request.

Author contributions

RA and GS designed and conducted the research, analyzed the data, and wrote the paper; DC and RS analyzed the samples and wrote the paper; JJB, SG, and MS initiated the research and wrote the paper; AL, NCS, AA, JR, AP, PD, and RT wrote the paper.

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Shah, G.L., Boelens, J.J., Carlow, D. et al. Population Pharmacokinetics of Melphalan in a Large Cohort of Autologous and Allogeneic Hematopoietic Cell Transplantation Recipients: Towards Individualized Dosing Regimens. Clin Pharmacokinet 61, 553–563 (2022). https://doi.org/10.1007/s40262-021-01093-z

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